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Spring 2006 Anticoagulants Page 1 of 21
ANTICOAGULANT, THROMBOLYTIC, and ANTI-PLATELET DRUGS
Katzung (9th ed.) Chapter 34 **** THIS VERSION HAS BEEN CHANGED COMPARED TO THE ONE MADE AVAILABLE ON WEDNESDAY APRIL 26 (sorry!) ****
(if med school is a Minnesota forest with millions of trees, these are the red pines)
These drugs are used to treat strokes, myocardial infarctions, pulmonary embolisms, disseminated intravascular coagulation (DIC) and deep vein thrombosis (DVT) --- all potentially life-threatening conditions. The effectiveness of thrombolytics (“clot busters”) is inversely related to the time elapsed since the thrombic crisis beganÆ these drugs are most effective within 6 hours of onset of symptoms. The major classes of anticoagulant drugs have distinctly different mechanisms of action, routes of administration and adverse effects. The mechanisms of action include: activation of anticlotting factors (especially antithrombin III), direct inhibition of thrombin, inhibition of synthesis of blood coagulation factor precursors (zymogens), and activation of protein C. A unique side effect to the use of HEPARIN is a transient thrombocytopenia (HIT) that occurs in 25% of patients. The approved use of direct thrombin inhibitors (DTIs) is for the treatment of heparin-induced thrombocytopenia (HIT). WARFARIN: • • • has a NARROW THERAPEUTIC INDEX is NEARLY COMPLETELY (99%) BOUND TO PLASMA ALBUMIN is ELIMINATED BY HEPATIC METABOLISM (cytP450)
4. 5. 6.
Æ WARFARIN IS THE PROTOTYPE FOR DRUG-DRUG INTERACTIONS! 7. DROTRECOGIN ALFA is approved for use in disseminated intravascular coagulation or DIC (fatal complication of septic shock). The use of activated protein C as a drug occurred as a result of a change in our understanding of the pathophysiology of sepsis, particularly the intricate interplay between activation of coagulation and inflammation.
Med 6541 Hematopoiesis and Host Defences Dr. Janet Fitzakerley 307 Med email@example.com www.d.umn.edu/~jfitzake
Spring 2006 Anticoagulants Page 2 of 21
DRUGS YOU NEED TO KNOW: ANTICOAGULANTS
ARGATROBAN BIVALIRUDIN (Angiomax) DALTEPARIN (Fragmin) DROTRECOGIN ALFA (ACTIVATED PROTEIN C) (Xigris) ENOXAPARIN (Lovenox) FONDAPARINUX HEPARIN (Calciparine, Hepathrom,
Lipo-Hepin, Liquaemin, Panheprin)
AMINOCAPROIC ACID (EACA) (generic, Amicar) (in bleeding disorders handout!)
ANISTREPLASE (APSAC; Eminase) STREPTOKINASE (Streptase, Kabikinase) TISSUE PLASMINOGEN ACTIVATORS (tPAs): ALTEPLASE (Activase), RETEPLASE (Retavase), TENECTEPLASE (TNKase) UROKINASE (Abbokinase)
HIRUDIN (Desirudin) 4-HYDROXYCOUMARIN (Coumadin) LEPIRUDIN (Refludan) WARFARIN (Athrombin-K, Panwarfin) XIMELAGATRAN (Exanta)
ABCIXIMAB (Centocor) ACETYLSALICYLIC ACID (Aspirin) CLOPIDOGREL (Plavix) DIPYRIDAMOLE (Persantine) EPTIFIBATIDE (Integrilin) TICLOPIDINE (Ticlid) TIROFIBAN (Aggrastat)
PHYTONADIONE (Vitamin K1) PROTAMINE SULFATE
IMPORTANT MATERIAL FROM OTHER LECTURES:
1. Principles of pharmacokinetics and pharmacodynamics, esp. therapeutic index, drug metabolism, the cytochrome P450 system (Dr. Knych, Principles), and types of biological variability (Dr. Eisenberg, Principles). Coagulation and thrombosis (Drs. Krafts and Prohaska, Hematopoiesis).
1. Be able to diagram the coagulation and fibrinolytic pathways and the interaction of protein C with those pathways. Define how different classes of anticoagulant and fibrinolytic drugs interact with specific clotting factors and naturally occurring anticoagulants in the context of these pathways. Be able to describe the biochemical mechanisms of action, therapeutic uses, contraindications and adverse effects of the specific anticoagulant and fibrinolytic agents listed above. Know the properties of agents that can reverse the actions of heparin and the oral anticoagulants.
pulmonary embolisms. Janet Fitzakerley 307 Med jfitzake@d. Be able to use cytochrome P450 interaction tables to identify the interactions of other drugs with both R. antidotes and use during pregnancy.umn.and S-warfarin. heparin and low molecular weight heparins heparin and warfarin 4. THERAPEUTIC STRATEGIES These drugs are used to treat strokes. Compare and contrast: a.d.all potentially life-threatening conditions. 5. method of monitoring. Be able to identify both the common and the distinguishing characteristics of thrombolytic agents. with respect to mechanism of action. its limitations and the agents that are currently approved for this purpose.edu/~jfitzake Spring 2006 Anticoagulants Page 3 of 21 3. myocardial infarctions.umn. Be able to describe specific pharmacokinetic and pharmacodynamic principles governing the interactions of warfarin with specific drugs listed in the main section of the handout. administration. Describe the empirical rationale for thrombolytic therapy.Med 6541 Hematopoiesis and Host Defences Dr. fibrinolytic and anti-inflammatory actions of drotrecogin alfa.edu www. • Degrade fibrinogen/fibrin (fibrinolytic agents) GOAL: eliminate formed clots • Inhibit clotting mechanism (anticoagulants) GOAL: prevent progression of thrombosis • Interfere either with platelet adhesion and/or aggregation (antiplatelet drugs) GOAL: prevent initial clot formation . 6. disseminated intravascular coagulation (DIC) and deep vein thrombosis (DVT) --. b. time to onset of activity. Understand why particular disease states and co-administration of other drugs can alter the efficacy and side effects of warfarin. Know the specifics of the anti-coagulant.
d.edu/~jfitzake Spring 2006 Anticoagulants Page 4 of 21 .Med 6541 Hematopoiesis and Host Defences Dr.umn.edu www. Janet Fitzakerley 307 Med firstname.lastname@example.org.
edu www. UROKINASE Common Features • dissolve existing lifethreatening thrombi • activate plasminogen to The effectiveness of thrombolytics is inversely related to the time elapsed since the thrombic crisis began Æ these drugs are most effective within 6 hours of onset of symptoms plasmin Æ hydrolysis of fibrin and several other coagulation factors • • • plasmin formed inside a thrombus is protected from plasma antiplasmins short activation times. history of hypertension (diastolic > 110 mmHg) 6. 4.Med 6541 Hematopoiesis and Host Defences Dr.umn. ANISTREPLASE. TENECTEPLASE. pregnancy 7.d. and short half-lives recommended for patients with: o o o o recent acute MI (selection of patients is critical!!! Some can be harmed) extensive pulmonary emboli severe deep vein thrombosis thromboembolic stroke (tPAs only) Common Contraindications/Precautions • cause BLEEDING (particularly hemorrhagic stroke) – can be antagonized by AMINOCAPROIC ACID (for tPAs) or APROTININ (for STREPTOKINASE) o inhibitory control system can be overwhelmed producing a systemic lytic state Æ not for use in: 1. 3. acute pericarditis • thrombolytic therapy is expensive (particularly tPAs) .umn. 2. STREPTOKINASE. Janet Fitzakerley 307 Med jfitzake@d. aortic dissection 8.edu/~jfitzake Spring 2006 Anticoagulants Page 5 of 21 THROMBOLYTIC DRUGS tPAs: ALTEPLASE. recent surgery (10 days) GI bleeding (3 months) active bleeding or hemorrhagic disorder previous cerebrovascular accident or active intracranial process 5. RETEPLASE.
UROKINASE Mechanism of Action • • kidney enzyme that directly converts plasminogen to active plasmin primarily indicated only for patients allergic to STREPTOKINASE Adverse Effects • febrile episodes are common but infusion reactions and hypersensitivity (anaphylaxis) are rare 3. ANISTREPLASE. TISSUE PLASMINOGEN ACTIVATORS (tPAs): ALTEPLASE.edu/~jfitzake Spring 2006 Anticoagulants Page 6 of 21 1.umn.edu www.more convenient (shorter infusion time) but far more expensive with an increased tendency for systemic thrombolysis Adverse Effects • may evoke allergic hypersensitivity reactions.Med 6541 Hematopoiesis and Host Defences Dr. Janet Fitzakerley 307 Med jfitzake@d. STREPTOKINASE Mechanism of Action • binds to and induces a conformational change in plasminogen resulting in exposure of the active site and conversion to plasmin (STREPTOKINASE itself is not intrinsically active) • ANISTREPLASE is an inactive complex of STREPTOKINASE and human lys-plasminogen . TENECTEPLASE • genetically engineered from human melanoma cells o o o ALTEPLASE is unmodified human tPA RETEPLASE has several amino acid sequences deleted TENECTEPLASE is a recombinant version of human tPA with 3 amino acid substitutions . fever and anaphylaxis 2.umn. RETEPLASE.d.
Med 6541 Hematopoiesis and Host Defences Dr.umn. i.umn.edu www. theoretically confines fibrinolysis to the formed thrombus and decreases systemic activation ANTICOAGULANT DRUGS The major classes of anticoagulant drugs have distinctly different mechanisms of action. .e.edu/~jfitzake Spring 2006 Anticoagulants Page 7 of 21 Mechanism of Action • • causes “selective” activation of fibrin-bound plasminogen poor plasminogen activator in the absence of fibrin.d. routes of administration and adverse effects.. Janet Fitzakerley 307 Med jfitzake@d.
Bind to antithrombin III. IX.g.umn.g. Activation of anticlotting factors (especially antithrombin III) e. 3.e. FONDAPARINUX Generalities HEPARIN • • • • • most commonly given anticoagulant for short term use (>12 million patients/year) is a complex mixture of mucopolysaccharides isolated from bovine lung or porcine intestine normally found in mast cells . DROTRECOGIN ALFA 1.g.edu www.e.unknown physiologic role strongly acidic DALTEPARIN. X and XI (i. HIRUDIN Inhibition of synthesis of blood coagulation factor precursors (zymogens) e.d. DRUGS THAT ACTIVATE ANTICLOTTING FACTORS: HEPARIN. ENOXAPARIN.edu/~jfitzake Spring 2006 Anticoagulants Page 8 of 21 Mechanisms of Action: 1. heparins are INDIRECT thrombin inhibitors) • • • conformational change in ATIII exposure of ATIII active site more rapid formation of ATIII-protease complexes .Med 6541 Hematopoiesis and Host Defences Dr... DALTEPARIN. Activated Protein C i.umn. 2. a protease inhibitor that complexes with activated clotting factors II. HEPARIN Direct inhibition of thrombin e. WARFARIN 4. ENOXAPARIN • low MW fragments of HEPARIN Fondaparinux • synthetic formulation of the key pentasaccharide that appears to be the active component in all heparins Mechanisms of Action 1. Janet Fitzakerley 307 Med jfitzake@d.
umn. IM administration causes hematomas) rapid effect (within minutes). release of HEPARIN.umn.edu/~jfitzake Spring 2006 Anticoagulants Page 9 of 21 • 2.Med 6541 Hematopoiesis and Host Defences Dr. instantaneously in vitro metabolized in liver. activated clotting factors remain bound to ATIII Coat blood vessel wall (prevents platelet binding or causes permeabilization?) Pharmacokinetics • • • • • activity is standardized by bioassay must be given IV (not active orally. ENOXAPARIN Greater than heparin • • • • Anti-factor Xa activity Bioavailability (SC administration) Half-life (decreased dosing) More predictable pharmacology (less need for monitoring) Less than heparin • • • • Inactivation of thrombin (IIa) Platelet inhibition Vascular permeabilization Plasma protein binding Therapeutic Indications • for an immediate hypothrombic response: o massive deep-vein thrombosis o pulmonary infarct o post-operative acute MI (except brain. excreted in urine HEPARIN dose is adjusted to double partial thromboplastin time (monitored by aPTT) DALTEPARIN. Janet Fitzakerley 307 Med jfitzake@d. spinal cord or eye) o prior to cardioversion of atrial fibrillation • effective anticoagulant in vitro Adverse Effects • • HEMORRHAGE (esp.d.edu www. hemorrhagic stroke) hypersensitivity .
increased clotting o mineralocorticoid deficiency PROTAMINE SULFATE • • • • highly basic peptide that combines with HEPARIN as an ion pair lasts about 2 hours routinely used following cardiac surgery and other vascular procedures excess protamine also has an anticoagulant effect.Med 6541 Hematopoiesis and Host Defences Dr. HEPARIN should be discontinued.d.edu/~jfitzake Spring 2006 Anticoagulants Page 10 of 21 • transient HIT occurs in about 25% of the patients during first 5 days of treatment – severe HIT occurs in 5% of patients o small % of patients develop antibody-mediated thrombocytopenia that is associated with thrombosis (paradoxical) o in those patients. and treatment initiated with HIRUDIN or LEPIRUDIN. but not WARFARIN (may exacerbate the prothrombotic state) A unique side effect to the use of heparin is a transient thrombocytopenia (HIT). Janet Fitzakerley 307 Med email@example.com www. • prolonged administration of high doses may cause o osteoporosis o progressive reduction in antithrombin III Æ decreased effectiveness.umn. since it can interact with platelets. fibrinogen and other plasma proteins • anaphylactic reactions can occur .approximately 1% of patients with diabetes mellitus who have received protamine-containing insulin experience anaphylaxis • cannot reverse many LMWH! .
7.d. HIRUDIN. which means they can reach and inactivate fibrin-bound thrombin inside clots 3. little effect on platelets or bleeding time elimination of HIT as a side effect of treatment not inactivated by platelet or plasma proteins more uniform potency and increased safety rebound coagulation after discontinuation of the drug is less likely with direct thrombin inhibitors Pharmacokinetics • given IV (note: XIMELAGATRAN is first oral agent in this class Æ promoted as a replacement for both WARFARIN and HEPARIN because of its immediate anticoagulant action • metabolized by hydrolysis in liver.umn.umn.ARGATROBAN and XIMELAGATRAN bind reversibly to the thrombin active site • advantages over HEPARIN: 1. 6. 5. excreted in urine . 2. BIVALIRUDIN. Janet Fitzakerley 307 Med firstname.lastname@example.org/~jfitzake Spring 2006 Anticoagulants Page 11 of 21 2.edu www. BIVALIRUDIN is a synthetic analogue • work by 1) inhibiting fibrin binding to thrombin and 2) interacting with the thrombin active site Æ inhibiting thrombin activity even in the presence of bound fibrin • ARGATROBAN is a synthetic derivative of L-arginine . the recombinant form. Mechanism of Action • HIRUDIN isolated LEPIRUDIN was from is originally leech. XIMELAGATRAN The approved use of DTIs is for the treatment of heparininduced thrombocytopenia (HIT). LEPIRUDIN. DIRECT THROMBIN INHIBITORS (DTIs): ARGATROBAN.Med 6541 Hematopoiesis and Host Defences Dr. inhibition of coagulation via a single mechanism of action actions are independent of antithrombin III. 4.
increased in patients with renal insufficiency.umn.and R. peak plasma drug concentration in < 1 hr WARFARIN is a racemic mixture of R. liver injury. CYP2C19 and CYP3A4 • several genes play a role in WARFARIN metabolism: .d. X) • also decreases the activity of protein C (activated by thrombin) – responsible for some side effects Pharmacokinetics WARFARIN: • has a NARROW THERAPEUTIC INDEX • is NEARLY COMPLETELY (99%) BOUND TO PLASMA ALBUMIN • is ELIMINATED BY HEPATIC METABOLISM (cytP450) Æ WARFARIN IS THE PROTOTYPE FOR DRUG-DRUG INTERACTIONS! • • • rapid.umn.edu www. complete absorption from GI.edu/~jfitzake Spring 2006 Anticoagulants Page 12 of 21 • monitored by aPTT – ARGATROBAN causes elevated INRs because of test interference. VII.and S-forms – S is the active enantiomer S.Med 6541 Hematopoiesis and Host Defences Dr. WARFARIN Mechanism of Action • • inhibit epoxide hydrase interfere with the synthesis of vitamin K and thus inhibits activation of vitamin K-dependent clotting factors (II. Janet Fitzakerley 307 Med jfitzake@d. DRUGS THAT INHIBIT SYNTHESIS OF COAGULATION FACTOR PRECURSORS: 4-HYDROXYCOUMARIN.WARFARIN are metabolized differently. S is metabolized primarily by CYP2C9. or recent trauma and/or treatment with other anticoagulants 3. IX. making the transition to warfarin difficult Adverse Effects • HEMORRHAGE: dose related. and R by CYP1A2.
allowing the achievement of stable blood levels more quickly than the current method of trialand-error dosing • defects in the coagulation cascade can also confer resistance to WARFARIN: the most common are: APC resistance (factor V Leiden). biological t½ 6-6O hrs small daily doses – adjustment of prothrombin time takes ~ 1 week Therapeutic Indications • rodenticides .Med 6541 Hematopoiesis and Host Defences Dr.d. protein S deficiency.edu/~jfitzake Spring 2006 Anticoagulants Page 13 of 21 • polymorphisms in CYP2C9 cause about 30% of patients to be slow metabolizers (causes Ï serum concentrations) • polymorphisms in the vitamin K epoxide reductase multiprotein complex (VKOR) can confer resistance (Ð serum concentrations) • recent clinical studies show that testing for CYP2C9 polymorphisms allows physicians to better predict the appropriate starting dose for WARFARIN.edu www.umn. antithrombin III deficiency • • no in vitro effect readily crosses placenta • • delayed hypothrombic effect (1-3 days). protein C deficiency. Janet Fitzakerley 307 Med email@example.com. t½ 35 hr.
edu www.d. rarely can progress to infarction (venous thrombosis) in fatty tissues.umn.umn.edu/~jfitzake Spring 2006 Anticoagulants Page 14 of 21 • • long-term oral treatment of deep-vein thrombosis for 2-6 months following myocardial infarction atrial fibrillation • Adverse Effects • • • HEMORRHAGE flatulence and diarrhea are common decreased protein C causes cutaneous necrosis caused during first weeks of treatment. Janet Fitzakerley 307 Med jfitzake@d.Med 6541 Hematopoiesis and Host Defences Dr. intestine and extremities • bone defects (chondrodysplasia punctata) and hemorrhagic disorders in infants born to mothers taking the drug during first trimester of pregnancy Æ ABSOLUTELY CONTRAINDICATED IN PREGNANCY .
Med 6541 Hematopoiesis and Host Defences Dr.umn. Janet Fitzakerley 307 Med firstname.lastname@example.org/~jfitzake Spring 2006 Anticoagulants Page 15 of 21 • DISEASE STATE and DRUG INTERACTIONS PHARMACOKINETIC PHARMACODYNAMIC • • • ABSORPTION ↑ binding in intestine • • • SYNERGISM ↓ platelet/clotting factor function DISTRIBUTION ↓ plasma protein binding ANTAGONISM ↑ concentration of clotting factors ELIMINATION cytP450 inhibition cytP450 induction ALTERED VITAMIN K ↓ availability of vitamin K .edu www.umn.
umn.Med 6541 Hematopoiesis and Host Defences Dr.d. Janet Fitzakerley 307 Med email@example.com www.umn.edu/~jfitzake Spring 2006 Anticoagulants Page 16 of 21 Drug Interactions Importance of Cytochrome P450 Isozymes .
miconzaole. the patient was still very sedated and dizzy. Janet Fitzakerley 307 Med firstname.lastname@example.org. GI drugs (esp. phytonadione. erythromycin. HIRUDIN. fluvoxamine. allopurinol. barbiturates. . sedative-hypnotics.Med 6541 Hematopoiesis and Host Defences Dr. carbamazepine. On the death of her husband. cimetidine. the woman was brought to the emergency department by her daughter. she presented with symptoms of depression and PAROXETINE was added to her medication regimen. cholestyramine. phenytoin Drugs that ALWAYS Interact with Warfarin • aspirin. HEPARIN. sulfonamides. thyroid medications • Specifically: abciximab. clofibrate. cimetidine. • Three days later. phenytoin Drugs that are LIKELY to be co-administered with Warfarin (due to co-morbidity. antiplatelet drugs. On awakening. She was again brought to the ER. noting that paroxetine had been added recently.umn. antihyperlipidemics. antibiotics/antifungals. the patient complained of dry mouth and dizziness. changed the patient to FLUVOXAMINE. diuretics. uricosurics (anti-gout). phenytoin.d. aspirin. • The ER physician. high prescription rate and/or OTC status) • By class: other anticoagulants.0. NSAIDS. metronidazole.edu www. fluconazole. cephalosporins. anti-arrhythmics. Her INR was 4. and complained of difficulty urinating. where bladder catheterization yielded two liters of dark urine. which he thought would be less sedating. cimetidine.edu/~jfitzake Spring 2006 Anticoagulants Page 17 of 21 ILLUSTRATIVE CASE • A 74-year-old woman with insulin-dependent (type 2) diabetes had been taking METOPROLOL and WARFARIN for atrial fibrillation and AMITRIPTYLINE for diabetic neuropathy for several years. lovastatin. analgesics and NSAIDS. “Classic” cytochrome P450 interactions • alcohol. gemfibrozil. antacids). alcohol (acute and chronic). who had found her asleep at 11 am. ciprofloxacin. • Three days after the initiation of paroxetine therapy.
gingko biloba. feverfew. Dalteparin.edu/~jfitzake Spring 2006 Anticoagulants Page 18 of 21 thyroid hormones. Lepirudin Decreased availability of vitamin K Cephalosporins Pharmacodynamic DECREASES in Effect Increased concentrations of clotting factors Diuretics Vitamin K .Med 6541 Hematopoiesis and Host Defences Dr.umn. dong quai. chamomile.edu www. Janet Fitzakerley 307 Med jfitzake@d. ginger. trimethoprim-sulfamethoxazole Many herbal supplements: black cohosh.d. ginseng (only one that decreases efficacy) Pharmacokinetic INCREASES in Effect Inhibition of metabolism Acute alcohol Allopurinol Cimetidine Ciprofloxacin Erythromicin Fluconazole Lovastatin Metronidazole Sulfonamides Trimethoprim-sulfamethoxazole Decreased Plasma Protein Binding Clofibrate Gemfibrozil Phenytoin (initially) Sulfonamides Trimethoprim-sulfamethoxazole Pharmacokinetic DECREASES in Effect Enzyme Induction Carbamazepine Chronic alcohol Phenytoin (ultimately) Decreased absorption Cholestyramine Pharmacodynamic INCREASES in Effect Decreased platelet/ clotting factor function Abciximab ASA Heparin.umn. Enoxaparin Hirudin. garlic.
2. ↓ clotting factor turnover 4. ↑ synthesis/function of clotting factors and/or platelets 3.umn. the most common of which are: APC resistance (factor V Leiden). protein S deficiency.umn. ↑ clotting factor turnover ↓ drug metabolism/elimination 1.Med 6541 Hematopoiesis and Host Defences Dr. ↑ drug metabolism/elimination * Hereditary resistance to warfarin has been shown to be due to defects in the coagulation cascade. 4. ↓ vitamin K levels ↓ synthesis/function of clotting factors and/or platelets 3.edu www. von Willebrand’s disease. thrombocytopenia) DECREASE ANTICOAGULANT EFFICACY Alcoholism (chronic) 4 Edema2 Hyperlipemia1 Hereditary resistance*2 Hypothyroidism3 Nephrotic syndrome4 Diarrhea1 Elevated temperature3 Hepatic disease2. antithrombin III deficiency PHYTONADIONE (Vitamin K1) • pharmacodynamic antagonist (not due to disappearance of warfarin. Janet Fitzakerley 307 Med jfitzake@d. ↑ vitamin K levels 2.4 Hyperthyroidism3 Inadequate diet1 (esp. but rather the reestablishment of normal clotting factor activity) – takes 24 hours • fresh-frozen plasma or factor IX concentrates are also effective .d. vitamin K deficiency) Jaundice2 Small bowel disease1 Steatorrhea1 1.edu/~jfitzake Spring 2006 Anticoagulants Page 19 of 21 DISEASE STATES INCREASE ANTICOAGULANT EFFICACY Blood dyscrasias2 (hemophilia. protein C deficiency.
Mechanism of Action • recombinant version of protein C. DROTRECOGIN ALFA (ACTIVATED PROTEIN C) DROTRECOGIN ALFA is approved for use in disseminated intravascular coagulation or DIC (fatal complication of septic shock).edu/~jfitzake Spring 2006 Anticoagulants Page 20 of 21 4.umn. activated by thrombin. particularly the intricate interplay between activation of coagulation and inflammation.edu www. resulting in ↓ thrombin formation inhibits platelet activation suppresses tissue factor expression fibrinolytic actions 1) 2) attenuates thrombin-catalyzed activation of tPA inhibitors decreases PAI-1 concentrations • anti-inflammatory actions: 1) 2) 3) inhibits synthesis of tumor necrosis factor inhibits neutrophil activation blocks the release of cytokines from macrophages Therapeutic Indications • decreases relative risk of death by 20% (up to 50% of patients die of sepsis within 6 months) Adverse Effects • HEMORRHAGE: dose related. phospholipid and protein S as cofactors • anti-coagulant actions: 1) 2) 3) • destroys activated factors Va and VIIIa. Janet Fitzakerley 307 Med jfitzake@d. no increase in patients with renal or liver insufficiency . The use of activated protein C as a drug occurred as a result of a change in our understanding of the pathophysiology of sepsis.d.Med 6541 Hematopoiesis and Host Defences Dr. requires Ca2+.umn.
TICLOPIDINE 4. TICLOPIDINE.g.g. DIPYRIDAMOLE. Inhibiting cyclooxygenase: e. CLOPIDOGREL. Janet Fitzakerley 307 Med email@example.com. ASA Blocking glycoprotein IIb/IIIa receptor: e. CLOPIDOGREL. EPTIFIBATIDE.umn.edu/~jfitzake Spring 2006 Anticoagulants Page 21 of 21 ANTIPLATELET DRUGS ASA. DIPYRIDAMOLE .Med 6541 Hematopoiesis and Host Defences Dr. TIROFIBAN Mechanisms of Action Inhibit platelet adhesion and aggregation by: 1.g. Inhibiting cyclic nucleotide phosphodiesterase: e. EPTIFIBATIDE Inhibiting the binding of fibrinogen to activated platelets: e. 3. 2.d.edu www. ABCIXIMAB. ABCIXIMAB.
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